Impairing anxiety affects 33% of the population by adolescence and can become chronic, leading to depression, substance abuse, school-drop out and even suicide. To reduce anxiety and prevent its sequelae, patients must be effectively treated early; yet, the first line intervention, cognitive behavioral therapy (CBT), has a heterogeneous response with 40-60% of treated patients continuing to experience impairment from residual symptoms. The reasons for variability in CBT outcomes remain poorly understood, but individual (including developmental) differences in brain-behavioral targets of CBT may contribute. This proposal addresses two fundamental and open questions: 1) Do individual differences in CBT-relevant brain-behavioral functions lead to variation in CBT outcomes? and 2) Does development contribute to this variation? By defining dimensional constructs at multiple levels of analysis, NIMH's RDoC provides a framework for identifying patient-specific mechanisms of CBT outcomes, across traditional, categorical anxiety disorders. The RDoC constructs of Cognitive Control (CC), Acute Threat (AT) and their interactions (CC-AT) shape the selection of putative brain- behavior targets of CBT for the proposed study. Given that CBT facilitates control over acute threat to enable effective regulation, we hypothesize that AT-, CC- and AT-CC-defined markers will predict and characterize mechanisms of CBT effect. In addition, based on emerging evidence (including our own pilot data) showing later development of neural substrate for cognitive control compared to earlier increase in brain reactivity to threat, we hypothesize that AT, CC, CC-AT markers will differentially relate to CBT effect, depending on patient age. These hypotheses will be tested by measuring data at multiple levels of analysis: brain function-structure (fMRI, DTI) and behavioral performance to index in AT, CC and CC-AT constructs, and clinical measures of anxiety in 280 youths. Of these, 210 youths with impairing anxiety will be randomized to receive CBT or a relaxation control therapy and multilevel data will be collected again after treatment. The project will connect developmental neuroscience and clinical trial research to enable a mechanistic understanding of how different patients at different ages benefit from CBT.